This study was conducted to determine the prevalence and determinants of medication adherence among patients with HIV/AIDS in southern Vietnam. Methods: A cross-sectional study was conducted in a hospital in southern Vietnam from June to December 2019 on patients who began antiretroviral therapy (ART) for at least 6 months. Using a designed questionnaire, patients were considered adherent if they took correct medicines with right doses, on time and properly with food and beverage and had follow-up visits as scheduled. Multivariable logistic regression was used to identify determinants of adherence. Key findings: A total of 350 patients (from 861 medical records) were eligible for the study. The majority of patients were male (62.9%), and the dominant age group (≥35 years old) accounted for 53.7% of patients. Sexual intercourse was the primary route of transmission of HIV (95.1%). The proportions of participants who took the correct medicine and at a proper dose were 98.3% and 86.3%, respectively. In total, 94.9% of participants took medicine appropriately in combination with food and beverage, and 75.7% of participants were strictly adherent to ART. The factors marital status (odds ratio (OR) = 2.54; 95%CI = 1.51–4.28), being away from home (OR = 1.7; 95%CI = 1.03–2.78), substance abuse (OR = 2.7; 95%CI = 1.44–5.05), general knowledge about ART (OR = 2.75; 95%CI = 1.67–4.53), stopping medication after improvement (OR = 4.16; 95%CI = 2.29–7.56) and self-assessment of therapy adherence (OR = 9.83; 95%CI = 5.44–17.77) were significantly associated with patients’ adherence. Conclusions: Three-quarters of patients were adherent to ART. Researchers should consider these determinants of adherence in developing interventions in further studies.